Lysosomal impairments in Pompe disease are associated with altered T cell homeostasis and intrinsic metabolic dysregulation

Lysosomal impairments in Pompe disease are associated with altered T cell homeostasis and intrinsic metabolic dysregulation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Lysosomal impairments in Pompe disease are associated with altered T cell homeostasis and intrinsic metabolic dysregulation Helena Costa-Verdera, Marco Gargaro, Umut Cagin, Giorgia Manni, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7329159/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Mar, 2026 Read the published version in Cellular and Molecular Life Sciences → Version 1 posted 5 You are reading this latest preprint version Abstract Pompe disease (PD) is a neuromuscular lysosomal storage disorder caused by mutations in the GAA gene, characterized by progressive glycogen accumulation in multiple tissues and autophagy and metabolic abnormalities. While immunological changes have largely been overlooked as part of PD's symptomatology, autophagy and metabolic regulation are crucial in immune cell function. High incidence of immune reactions against therapeutic recombinant GAA (rhGAA) in PD patients suppose an important hindrance to treatment efficacy, yet the impact of GAA deficiency on the immune system remains unclear. We hypothesized that metabolic and autophagy defects in PD extend to immune cells, exacerbating immune reactions against rhGAA. Here we explored the T cell phenotype in late-onset PD patient cells and in a PD mouse model, revealing heightened expression of activation markers in effector T cells compared to controls. Additionally, we observed decreased frequencies of regulatory T cells in mice. Mechanistically, Gaa -/- T cells reproduced autophagy and mitophagy defects reported in muscle cells, and upon stimulation, T cells showed impaired mitochondrial function consistent with defective mitophagy. Preliminary findings also suggest that alterations translate to a subset of CD24 + CD172 - conventional dendritic cells with regulatory function, which could indirectly contribute to higher T cell activation. Our observations indicate that immune homeostasis is altered in PD, offering new insights on immune dysfunction in the context of lysosomal impairment and supporting its potential role in the pathogenesis of PD. Pompe disease lysosomal storage disease autophagy mitophagy T cells Tregs Full Text Supplementary Files CostaVerderaGargaroetal.SupplementaryMaterialsA4.pdf Cite Share Download PDF Status: Published Journal Publication published 16 Mar, 2026 Read the published version in Cellular and Molecular Life Sciences → Version 1 posted Editorial decision: Minor Revision 17 Oct, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers invited by journal 14 Sep, 2025 Editor assigned by journal 21 Aug, 2025 First submitted to journal 20 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7329159","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":514941728,"identity":"2019218e-a3a9-4a47-a40c-898d8f710692","order_by":0,"name":"Helena 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dysregulation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pompe disease, lysosomal storage disease, autophagy, mitophagy, T cells, Tregs","lastPublishedDoi":"10.21203/rs.3.rs-7329159/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7329159/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePompe disease (PD) is a neuromuscular lysosomal storage disorder caused by mutations in the \u003cem\u003eGAA\u003c/em\u003e gene, characterized by progressive glycogen accumulation in multiple tissues and autophagy and metabolic abnormalities. While immunological changes have largely been overlooked as part of PD's symptomatology, autophagy and metabolic regulation are crucial in immune cell function. High incidence of immune reactions against therapeutic recombinant GAA (rhGAA) in PD patients suppose an important hindrance to treatment efficacy, yet the impact of GAA deficiency on the immune system remains unclear. We hypothesized that metabolic and autophagy defects in PD extend to immune cells, exacerbating immune reactions against rhGAA. Here we explored the T cell phenotype in late-onset PD patient cells and in a PD mouse model, revealing heightened expression of activation markers in effector T cells compared to controls. Additionally, we observed decreased frequencies of regulatory T cells in mice. Mechanistically, \u003cem\u003eGaa\u003c/em\u003e\u003csup\u003e-/-\u003c/sup\u003e T cells reproduced autophagy and mitophagy defects reported in muscle cells, and upon stimulation, T cells showed impaired mitochondrial function consistent with defective mitophagy. Preliminary findings also suggest that alterations translate to a subset of CD24\u003csup\u003e+\u003c/sup\u003eCD172\u003csup\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/sup\u003e conventional dendritic cells with regulatory function, which could indirectly contribute to higher T cell activation. Our observations indicate that immune homeostasis is altered in PD, offering new insights on immune dysfunction in the context of lysosomal impairment and supporting its potential role in the pathogenesis of PD.\u003c/p\u003e","manuscriptTitle":"Lysosomal impairments in Pompe disease are associated with altered T cell homeostasis and intrinsic metabolic dysregulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 08:49:48","doi":"10.21203/rs.3.rs-7329159/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor Revision","date":"2025-10-17T09:10:09+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-09-15T09:36:03+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-15T00:44:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-21T16:24:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular and Molecular Life Sciences","date":"2025-08-20T07:46:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a9259936-4b95-4c08-baaf-902572ffc678","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T16:06:01+00:00","versionOfRecord":{"articleIdentity":"rs-7329159","link":"https://doi.org/10.1007/s00018-026-06135-y","journal":{"identity":"cellular-and-molecular-life-sciences","isVorOnly":false,"title":"Cellular and Molecular Life Sciences"},"publishedOn":"2026-03-16 15:58:09","publishedOnDateReadable":"March 16th, 2026"},"versionCreatedAt":"2025-09-22 08:49:48","video":"","vorDoi":"10.1007/s00018-026-06135-y","vorDoiUrl":"https://doi.org/10.1007/s00018-026-06135-y","workflowStages":[]},"version":"v1","identity":"rs-7329159","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7329159","identity":"rs-7329159","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}